Transmissible spongiform encephalopathies (prion diseases) are characterized by the accumulation in the infected brains of an abnormal isoform of a host-encoded membrane glycoprotein (PrPC). The conversion of PrPC into the infectious form (scrapie isoform, PrPSc), by a conformational transition, is thought to be the key factor in the pathogenesis of spongiform encephalopathies. To understand the molecular basis of this transition, it is essential to compare the native secondary and tertiary structures of PrPSc and PrPC. Using circular dichroism, fluorescence and solid state Fourier transform- infrared spectroscopy we have studied the conformation of PrPC purified in native condition. The data obtained from the secondary structure analysis agreed with those predicted from the primary structure, with a similar contribution of alpha-helix and beta--sheets (approximately 26% and 19%, respectively) for the protein solubilized using the mild detergent octylglucoside. The use of a different detergent as zwitterion 3-14 drastically modifies PrP secondary structure (contribution of alpha-helix and beta-sheets approximately 41% and 0%, respectively). FT-IT and fluorescence data confirm a difference in PrP secondary structure related to the different solvent condition used. This is the first time that the possibility to modify PrPC secondary structure, depending on the environment, has been demonstrated.